Pharmaceutical solid preparations are sometimes coated with a sustained-release film-coating with a view to reducing side effects, reducing the administration frequency, improving the effect of the drug, or the like. The film coating can be applied to a tablet or a granular agent, and often applied to the granular agent in order to reduce the variability of the effects. In particular, in the case of sustained-release film coating, since it is necessary to exhaustively control the dissolution rate of the drug, spherical elementary granules having a uniform particle diameter are often used. Furthermore, since the most preferred dosage form in the pharmaceutical preparations by a patient is a tablet, it is desired that other excipients be added to the film-coated granules to form a tablet.
The general technique for making a tablet is compression with a tableting machine. In order to ensure the practical productivity, manageability and transport properties of tablets, it is necessary to increase tablet hardness by compression with a certain level of pressure. However, often this pressure damages a film of the film-coated granules and impairs the functions thereof. Therefore, attempts to find a solution to the problem by coating with a plurality of films and the like have been made.
It is very advantageous in terms of productivity to finish a film-coating process with one kind of film. One method that allows a film to withstand mechanical stress upon tableting is to provide the film with flexibility like rubber. However, a highly flexible film also has high tackiness on the film surface, and thus agglomeration of granules is likely to occur on film coating. In order to prevent the agglomeration of granules on film coating, while there are coping strategies such as using large granules, reducing the coating rate of the film-coating liquid, and adding a tackiness-reducing agent such as talc to the film-coating liquid, it is conventionally difficult to cope with various sizes of granules without sacrificing the productivity and film properties (drug-dissolution control, mechanical strength).
It is known that a film made from an ethyl acrylate/methyl methacrylate copolymer dispersion and a vinyl acetate polymer dispersion is very flexible. However, the film has high tackiness on the surface, and thus practical film coating has been difficult unless a tackiness-reducing agent such as talc is added. And in particular, the film coating on the granules having an average particle diameter of 300 μm or less has been very difficult.
PATENT DOCUMENT 1 discloses a technology for film-coating granules in the size range of 0.1 to 2 mm with a film-coating agent in which an ethyl cellulose aqueous dispersion and an antistatic agent (talc, light anhydrous silicic acid) are added to an ethyl acrylate/methyl methacrylate copolymer dispersion, mixing the film-coated granules with other excipients, and tableting the mixture. However, in Examples, only examples with spherical granules having a small size of 0.2 to 0.5 mm and a large size of 0.5 to 1.2 mm are shown. Since these granules have an average particle diameter of about 300 μm or more, it can be said that these granules were comparatively easy to be film-coated. Therefore, when small granules having an average particle diameter of 300 μm or less are film-coated with the film-coating agent of the above composition, the agglomeration often occurs for the tackiness of a film base. In addition, the above PATENT DOCUMENT 1 does not show an example relating to tableting and also does not refer anything for the increase in the drug-dissolution rate after tableting.
PATENT DOCUMENT 2 discloses a technology for film-coating granules with a size of 0.5 to 1.5 mm or 0.7 to 1.5 mm with a film-coating agent in which propylene glycol and talc are added to a polyvinyl acetate polymer dispersion. Since these granules also have an average particle diameter of 300 μm or more, these granules were considerably easy to be coated.
NON-PATENT DOCUMENT 1 discloses a technology for film-coating granules having a size of 500 μm or more with a film-coating agent in which triethyl citrate is added to a vinyl acetate polymer dispersion, mixing the film-coated granules with crystalline cellulose, and tableting the mixture. While the film of the above composition has very high tackiness and normally has a problem of the agglomeration of granules, it is considered that the granules could be film-coated since the used granules were large.    PATENT DOCUMENT 1: JP62-029514A    PATENT DOCUMENT 2: U.S. Pat. No. 7,094,831    NON-PATENT DOCUMENT 1: A. Dashevsky, K. Kolter, R. Bodomeier, Compression of pellets coated with various aqueous polymer dispersions, Int. J. Pharm., 2004, vol. 279, p. 19-26